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Molecular Alliance—From Orthosteric and Allosteric Ligands to Dualsteric/Bitopic Agonists at G Protein Coupled Receptors
Author(s) -
Mohr Klaus,
Schmitz Jens,
Schrage Ramona,
Tränkle Christian,
Holzgrabe Ulrike
Publication year - 2013
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201205315
Subject(s) - allosteric regulation , g protein coupled receptor , receptor , functional selectivity , chemistry , microbiology and biotechnology , g protein , intracellular , signal transduction , extracellular , allosteric modulator , biophysics , biochemistry , biology
Abstract Cell‐membrane‐spanning G protein coupled receptors (GPCRs) belong to the most important therapeutic target structures. Endogenous transmitters bind from the outer side of the membrane to the “orthosteric” binding site either deep in the binding pocket or at the extracellular N‐terminal end of the receptor protein. Exogenous modulators that utilize a different, “allosteric”, binding site unveil a pathway to receptor subtype‐selectivity. However, receptor activation through the orthosteric area is often more powerful. Recently there has been evidence that orthosteric/allosteric, in other words “dualsteric”, hybrid compounds unite subtype selectivity and receptor activation. These “bitopic” modulators channelreceptor activation and subsequent intracellular signaling into a subset of possible routes. This concept offers access to GPCR modulators with an unprecedented receptor‐subtype and signaling selectivity profile and, as a consequence, to drugs with fewer side effects.